Estimation of time since exposure for a prevalent cohort.
In natural history studies of human immunodeficiency virus type 1 (HIV-1) infection a substantial proportion of participants are seropositive at time of enrollment in the study. These participants form a prevalent subcohort. Estimation of the unknown times since exposure to HIV-1 in the prevalent subcohort is of primary importance for estimation of the incubation time of AIDS. The subset of the cohort that tested negative for antibody to HIV-1 at study entry and was observed to seroconvert forms the incident subcohort that provides longitudinal data on markers of maturity (that is, duration) of infection. We use parametric life table regression models incorporating truncation to describe the conditional distribution (imputing model) of the times since seroconversion given a vector of the markers of maturity. Using the fitted model and the values of the markers of maturity of infection provided by the seroprevalent subcohort at entry into the study, we can impute the unknown times since seroconversion for the prevalent subcohort. We implement multiple imputation based on a model-robust estimate of the covariance matrix of parameters of the imputing model to provide confidence intervals for the geometric mean of the time since seroconversion in the prevalent subcohort, and to compare maturity of infection of cohorts recruited in different cities. The accuracy of imputation is further validated by comparisons of imputation-based estimates of AIDS incubation distribution in the seroprevalent subcohort with more direct estimates obtained from the seroincident subcohort.


Strengthening Anti-Glioblastoma Effect by Multi-Branched Dendrimers Design of a Scorpion Venom Tetrapeptide.
Glioblastoma is the most aggressive and invasive form of central nervous system tumors due to the complexity of the intracellular mechanisms and molecular alterations involved in its progression. Unfortunately, current therapies are unable to stop its neoplastic development. In this context, we previously identified and characterized AaTs-1, a tetrapeptide (IWKS) from Androctonus autralis scorpion venom, which displayed an anti-proliferative effect against U87 cells with an IC50 value of 0.57 mM. This peptide affects the MAPK pathway, enhancing the expression of p53 and altering the cytosolic calcium concentration balance, likely via FPRL-1 receptor modulation. In this work, we designed and synthesized new dendrimers multi-branched molecules based on the sequence of AaTs-1 and showed that the di-branched (AaTs-1-2B), tetra-branched (AaTs-1-4B) and octo-branched (AaTs-1-8B) dendrimers displayed 10- to 25-fold higher effects on the proliferation of U87 cells than AaTs-1. We also found that the effects of the newly designed molecules are mediated by the enhancement of the ERK1/2 and AKT phosphorylated forms and by the increase in p53 expression. Unlike AaTs-1, AaTs-1-8B and especially AaTs-1-4B affected the migration of the U87 cells. Thus, the multi-branched peptide synthesis strategy allowed us to make molecules more active than the linear peptide against the proliferation of U87 glioblastoma cells.


Characteristics and Long-Term Outcome of Neurosarcoidosis: A Population-Based Study from 1976-2013.
Neurosarcoidosis is a rare condition with serious health consequences. However, little is known about clinical characteristics and outcome of neurosarcoidosis in the community setting. Patients with neurosarcoidosis were identified from a previously described cohort of patients with incident sarcoidosis from Olmsted County, Minnesota, United States from 1976 to 2013 using individual medical record review. Data on clinical characteristics, treatment, and outcome were collected. Neurological involvement by sarcoidosis occurred in 11 patients (3% of all patients with sarcoidosis). Cranial neuropathy was the most common type of neurological disease (5 patients; 45%) followed by peripheral neuropathy (3 patients; 27%), and meningitis (3 patients; 27%). Cerebrospinal fluid (CSF) pleocytosis and elevated CSF protein levels were observed in patients with meningitis, intramedullary spinal cord sarcoidosis, intracranial mass lesion and some patients with cranial neuropathy but were normal in patients with peripheral neuropathy. All patients received high-dose glucocorticoids as initial treatment and almost all responded to this therapy. Relapse after glucocorticoid dose reduction necessitated subsequent treatment with steroid-sparing agents in 4 patients. Neurosarcoidosis is an uncommon manifestation of sarcoidosis. Neurosarcoidosis manifestations generally responded well to high-dose glucocorticoids in the majority of patients, but relapse was common.


Sorafenib, a multikinase inhibitor, enhances the response of melanoma to regional chemotherapy.
Melanoma responds poorly to standard chemotherapy due to its intrinsic chemoresistance. Multiple genetic and molecular defects, including an activating mutation in the BRaf kinase gene, are associated with melanoma, and the resulting alterations in signal transduction pathways regulating proliferation and apoptosis are thought to contribute to its chemoresistance. Sorafenib, a multikinase inhibitor that targets BRaf kinase, is Food and Drug Administration approved for use in advanced renal cell and hepatocellular carcinomas. Although sorafenib has shown little promise as a single agent in melanoma patients, recent clinical trials suggest that, when combined with chemotherapy, it may have more benefit. We evaluated the ability of sorafenib to augment the cytotoxic effects of melphalan, a regional chemotherapeutic agent, and temozolomide, used in systemic and regional treatment of melanoma, on a panel of 24 human melanoma-derived cell lines and in an animal model of melanoma. Marked differences in response to 10 micromol/L sorafenib alone were observed in vitro across cell lines. Response to sorafenib significantly correlated with extracellular signal-regulated kinase (ERK) downregulation and loss of Mcl-1 expression (P < 0.05). Experiments with the mitogen-activated protein kinase/ERK kinase inhibitor U0126 suggest a unique role for ERK downregulation in the observed effects. Sorafenib in combination with melphalan or temozolomide led to significantly improved responses in vitro (P < 0.05). In the animal model of melanoma, sorafenib in combination with regional melphalan or regional temozolomide was more effective than either treatment alone in slowing tumor growth. These results show that sorafenib in combination with chemotherapy provides a novel approach to enhance chemotherapeutic efficacy in the regional treatment of in-transit melanoma.


A study of the contractility, biochemistry and morphology of an isolated preparation of human skeletal muscle.
1. A new method of studying isolated human skeletal muscle has been evaluated. This involves the incubation and electrical stimulation of strips of muscle, obtained at surgical biopsy, that are tied at the cut ends of the fibre bundles. 2. Morphological examination showed that the fibres were sealed off at the cut ends. Damage appeared to be restricted to the areas immediately adjacent to the ties. 3. Contractile properties were well maintained for several hours and measurements of tissue metabolites showed that muscle contents of the high-energy phosphate compounds were well preserved. 4. The isolated preparations were found to have the same contractile properties as human quadriceps femoris studied in vivo by the methods described in the preceeding paper. 5. Correlation was found between the relaxation speed of the isolated preparations and their fibre-type composition histochemically determined. 6. It is concluded that this technique is a valid addition to the present methods of studying the physiology and pharmacology of human skeletal muscle.


Rotational Doppler-effect due to selective excitation of vector-vortex field in optical fiber.
Experimental demonstration of rotational Doppler-effect due to direct and simultaneous excitation of orthogonal elliptically-polarized fundamental and vortex modes in a two-mode optical fiber is presented here. The rotation frequency and the trajectory of the zero-intensity point in the two-mode fiber output beam measured as a function of analyzer rotation matches with the S-contour of polarization singularity in the beam, identified via Stokes parameter measurement. The characteristics of the S-contour around the C-point in the output beam is also measured as a function of rotating Dove prism and half-wave plate - Dove prism combination to highlight the role of polarization modifying components on the observed rotational Doppler-effect of vector-vortex beams.


Large-scale assessment of 7-11-year-olds' cognitive and sensorimotor function within the Born in Bradford longitudinal birth cohort study.
Background: Cognitive ability and sensorimotor function are crucial aspects of children's development, and are associated with physical and mental health outcomes and educational attainment. This paper describes cross-sectional sensorimotor and cognitive function data collected on over 15,000 children aged 7-10 years, collected as part of the Born in Bradford (BiB) longitudinal birth-cohort study. Methodological details of the large-scale data collection process are described, along with initial analyses of the data involving the relationship between cognition/sensorimotor ability and age and task difficulty, and associations between tasks. Method: Data collection was completed in 86 schools between May 2016 and July 2019. Children were tested at school, individually, using a tablet computer with a digital stylus or finger touch for input. Assessments comprised a battery of three sensorimotor tasks (Tracking, Aiming, & Steering) and five cognitive tasks (three Working Memory tasks, Inhibition, and Processing Speed), which took approximately 40 minutes. Results: Performance improved with increasing age and decreasing task difficulty, for each task. Performance on all three sensorimotor tasks was correlated, as was performance on the three working memory tasks. In addition, performance on a composite working memory score correlated with performance on both inhibition and processing speed. Interestingly, within age-group variation was much larger than between age-group variation. Conclusions: The current project collected computerised measures of a range of cognitive and sensorimotor functions at 7-10 years of age in over 15,000 children. Performance varied as expected by age and task difficulty, and showed the predicted correlations between related tasks. Large within-age group variation highlights the need to consider the profile of individual children in studying cognitive and sensorimotor development. These data can be linked to the wider BiB dataset including measures of physical and mental health, biomarkers and genome-wide data, socio-demographic information, and routine data from local health and education services.


B-lymphocyte heterogeneity: ontogenetic development and organ distribution of B-lymphocyte populations defined by their density of surface immunoglobulin.
The density of total Ig and of IgM, IgG1, IgG2, and IgA on the surface of adult murine splenic B lymphocytes was measured using the technique of rapid flow microfluorometry. In addition, the density of total surface Ig and of IgM on B lymphocytes derived from adult bone marrow, lymph nodes, and Peyer's patches, and from neonatal spleen was determined. Adult spleen and lymph node B lymphocytes are characterized by the presence of a large population of cells with a low-to-intermediate density of total surface Ig, which is seen as a peak in the fluorescence profiles when these cells are labeled with fluorescein-conjugated (F1) anti-Ig. This peak is not detected when neonatal spleen or adult bone marrow are examined; the development of this peak among spleen cells occurs during the first 4 wk of life. Although the characteristic fluorescence intensity peak is not seen when adult spleen cells are labeled with Fl anti-mu, changes in the density of surface IgM do occur during the first few weeks of life and are detected as a decrease in the frequency of cells which have relatively large amounts of surface IgM. The differences seen in the fluorescence patterns of adult spleen cells labeled with Fl anti-Ig and Fl anti-mu may be due to the appearance of IgD on the surface of mature splenic B lymphocytes. This is supported by the similarity of the fluorescence profiles of adult bone marrow cells stained with Fl anti-Ig and Fl anti-mu, as the latter population of cells is reported to lack surface IgD.


The impact of co-morbidities on age-related differences in mortality after acute traumatic spinal cord injury.
Despite the shift in demographics of spinal cord injury (SCI) due to an aging population, relatively little has been reported regarding the effect of age on outcomes after SCI. This study examines the potential confounding effect of co-morbidities on the age-related differences in the hospital mortality following acute traumatic SCI. All consecutive patients with SCI who were admitted to our spine center from 1996 to 2007 were included. Co-morbidities were classified using the Charlson Co-morbidity Index (CCI), Cumulative Illness Rating Scale, and the number of ICD-9 codes. Major potential confounders included age, gender, co-morbidity, and level and severity of SCI. There were 217 males and 80 females with ages from 15 to 96 years. Most patients had an incomplete cervical SCI following falls or motor vehicle accidents. The mean in-hospital mortality rate was 5.7%. Using univariate analyses, older age, relevant pre-existing medical conditions, and motor complete SCI were major risk factors for in-hospital death after acute SCI. Among the three co-morbidity assessments, the CCI was the most reliable co-morbidity index for prediction of hospital mortality in SCI patients after controlling for age in the Cox proportional hazard modeling. In addition, the CCI appears to be a major confounder, which accounts for the majority of age-related differences in mortality following SCI. Our findings have implications for future clinical trials of therapies for adult patients with acute SCI and for management strategies of elderly individuals with SCI.


Is community-acquired pneumonia an independent risk factor for cardiovascular disease?
Community-acquired pneumonia (CAP) is the most frequent infectious cause of death in western countries. The high mortality rate in CAP is commonly related to comorbid conditions such as cardiovascular disease. Clinical studies in both primary and secondary care settings have identified an increase in short- and long-term risk of cardiovascular events and death from vascular events following acute respiratory infections. The mechanism remains to be fully established, but it has been suggested that the inflammatory state in patients affected by CAP acts to promote platelet activation and thrombosis, and to narrow coronary arteries through vasoconstriction. Acute infections destabilise vascular endothelium and create an imbalance between myocardial oxygen supply and demand, leading to an increased risk of cardiovascular events. Acute infections have been shown to have both systemic effects and local effects on coronary vessels. These effects are mediated through both the host response to infection and, in some cases, direct effects of bacterial infection or bacterial products. In this review, we discuss the link between CAP and increased risk of cardiovascular events, drawing on existing evidence from clinical and mechanistic studies. Further studies into and increased awareness of this association is warranted to promote novel ways of protecting high-risk patients.


Quantitative effects of male age on sperm motion.
Semen quality is associated with fertility status, but there is little quantitative information on risk factors that affect semen quality, especially in non-clinical populations. Advancing male age has been associated with a decline in semen quality, with the largest effect being on sperm motility. However, there is little quantitative data on the specific components of sperm motion that are affected by male age. We performed linear regression analyses of 14 aspects of semen quality measured by computer-assisted semen analysis (CASA) in a non-clinical cohort of 90 non-smoking men, aged 22-80 years, who had no history of infertility or reproductive problems. We found age-associated declines in CASA-determined motility (% motile, 0.8% per year; % progressively motile, 0.9% per year; % rapidly motile, 0.4% per year, P <or= 0.001) and three quantitative aspects of sperm motion [linearity (LIN), 0.2% per year; straight line velocity (VSL), 0.2% per year, and average path velocity (VAP), 0.3% per year, P < 0.05], with no evidence for age thresholds and no significant association with abstinence duration. Age was not significantly associated with amplitude of lateral head (ALH) displacement, beat cross frequency (BCF) and nuclear elongation or size. Quantitative analysis of sperm motion indicates that as men age, they produce fewer motile sperm, which are able to travel less along a linear path, thus covering less forward distance per unit time. These findings may have fertility implications for men who choose to delay fatherhood.


Optogenetic Tuning Reveals Rho Amplification-Dependent Dynamics of a Cell Contraction Signal Network.
Local cell contraction pulses play important roles in tissue and cell morphogenesis. Here, we improve a chemo-optogenetic approach and apply it to investigate the signal network that generates these pulses. We use these measurements to derive and parameterize a system of ordinary differential equations describing temporal signal network dynamics. Bifurcation analysis and numerical simulations predict a strong dependence of oscillatory system dynamics on the concentration of GEF-H1, an Lbc-type RhoGEF, which mediates the positive feedback amplification of Rho activity. This prediction is confirmed experimentally via optogenetic tuning of the effective GEF-H1 concentration in individual living cells. Numerical simulations show that pulse amplitude is most sensitive to external inputs into the myosin component at low GEF-H1 concentrations and that the spatial pulse width is dependent on GEF-H1 diffusion. Our study offers a theoretical framework to explain the emergence of local cell contraction pulses and their modulation by biochemical and mechanical signals.


Crystal orientation of PEO confined within the nanorod templated by AAO nanochannels.
The orientation of poly(ethylene oxide) (PEO) crystallites developed in the nanochannels of anodic aluminum oxide (AAO) membrane has been investigated. PEO was filled homogeneously into the nanochannels in the melt state, and the crystallization confined within the PEO nanorod thus formed was allowed to take place subsequently at different temperatures. The effects of PEO molecular weight (MPEO), crystallization temperature (Tc) and AAO channel diameter (DAAO) on the crystal orientation attained in the nanorod were revealed by 2-D wide angle X-ray scattering (WAXS) patterns. In the nanochannels with DAAO = 23 nm, the crystallites formed from PEO with the lowest MPEO (= 3400 g mol-1) were found to adopt a predominantly perpendicular orientation with the crystalline stems aligning normal to the channel axis irrespective of Tc (ranging from -40 to 20 °C). Increasing MPEO or decreasing Tc tended to induce the development of the tilt orientation characterized by the tilt of the (120) plane by 45° from the channel axis. In the case of the highest MPEO (= 95 000 g mol-1) studied, both perpendicular and tilt orientations coexisted irrespective of Tc. Coexistent orientation was always observed in the channels with a larger diameter (DAAO = 89 nm) irrespective of MPEO and Tc. Compared with the previous results of the crystal orientation attained in nanotubes templated by the preferential wetting of the channel walls by PEO, the window of the perpendicular crystal orientation in the nanorod was much narrower due to its weaker confinement effect imposed on the crystal growth than that set by the nanotube.


Human and mouse mast cells express and secrete the GPI-anchored isoform of CD160.
CD160 is expressed by human and mouse natural killer (NK) cells and other cytotoxic lymphocyte subpopulations. CD160 is mostly expressed as a trimeric 83 kDa glycosylphosphatidylinositol (GPI)-anchored activating NK receptor, cleaved upon IL-15 stimulation in a secreted trimeric soluble form (sCD160) that binds to major histocompatibility complex (MHC) class I molecules, while a transmembrane isoform appears. sCD160 exhibits immunoregulatory function as it inhibits CD8(+) T-lymphocyte cytotoxic activity. We show that human mast cells (MCs) express CD160. In human and mouse skin, resident MCs expressed CD160, whereas in C57BL/6-Kit(W-sh/W-sh) mice, CD160(+) cells were only identified at the site of reconstitution with syngeneic cultured MCs. In the human mast cell line, HMC-1, we only identified the transcripts of the GPI-anchored CD160 isoform. Furthermore, CD160 was identified in HMC-1 and mouse MC supernatants, suggesting that MCs release sCD160. Supporting this hypothesis, HMC-1 express the GPI-specific phospholipase D variant 2 involved in the NK lymphocyte membrane cleavage of CD160, and morphological studies highlighted a relative loss of CD160 expression in inflammatory skin sites, where MC degranulation is expected to occur. We also demonstrated an inhibition of T-cell cytotoxicity by HMC-1 supernatant that was partially reversed by anti-CD160 mAb. In conclusion, sCD160, produced by MCs, may have a role in T-cell-MC interactions in vivo.


Adherence to the Mediterranean diet and risk of bladder cancer in the EPIC cohort study.
There is growing evidence of the protective role of the Mediterranean diet (MD) on cancer. However, to date no epidemiological study has investigated the influence of the MD on bladder cancer. We evaluated the association between adherence to the MD and risk of urothelial cell bladder cancer (UCC), according to tumor aggressiveness, in the European Prospective Investigation into Cancer and Nutrition (EPIC). The analysis included 477,312 participants, recruited from ten European countries between 1991 and 2000. Information from validated dietary questionnaires was used to develop a relative Mediterranean diet score (rMED), including nine dietary components. Cox regression models were used to assess the effect of the rMED on UCC risk, while adjusting for dietary energy and tobacco smoking of any kind. Stratified analyses were performed by sex, BMI, smoking status, European region and age at diagnosis. During an average follow-up of 11 years, 1,425 participants (70.9% male) were diagnosed with a first primary UCC. There was a negative but non-significant association between a high versus low rMED score and risk of UCC overall (HR: 0.84 [95% CI 0.69, 1.03]) and risk of aggressive (HR: 0.88 [95% CI 0.61, 1.28]) and non-aggressive tumors (HR: 0.78 [95% CI 0.54, 1.14]). Although there was no effect modification in the stratified analyses, there was a significant 34% (p = 0.043) decreased risk of UCC in current smokers with a high rMED score. In EPIC, the MD was not significantly associated with risk of UCC, although we cannot exclude that a MD may reduce risk in current smokers.


Alcohol use among female sex workers and male clients: an integrative review of global literature.
To review the patterns, contexts and impacts of alcohol use associated with commercial sex reported in the global literature. We identified peer-reviewed English-language articles from 1980 to 2008 reporting alcohol consumption among female sex workers (FSWs) or male clients. We retrieved 70 articles describing 76 studies, in which 64 were quantitative (52 for FSWs, 12 for male clients) and 12 qualitative. Studies increased over the past three decades, with geographic concentration of the research in Asia and North America. Alcohol use was prevalent among FSWs and clients. Integrating quantitative and qualitative studies, multilevel contexts of alcohol use in the sex work environment were identified, including workplace and occupation-related use, the use of alcohol to facilitate the transition into and practice of commercial sex among both FSWs and male clients, and self-medication among FSWs. Alcohol use was associated with adverse physical health, illicit drug use, mental health problems, and victimization of sexual violence, although its associations with HIV/sexually transmitted infections and unprotected sex among FSWs were inconclusive. Alcohol use in the context of commercial sex is prevalent, harmful among FSWs and male clients, but under-researched. Research in this area in more diverse settings and with standardized measures is required. The review underscores the importance of integrated intervention for alcohol use and related problems in multilevel contexts and with multiple components in order to effectively reduce alcohol use and its harmful effects among FSWs and their clients.


The C-terminal domain of Fcj1 is required for formation of crista junctions and interacts with the TOB/SAM complex in mitochondria.
Crista junctions (CJs) are tubular invaginations of the inner membrane of mitochondria that connect the inner boundary with the cristae membrane. These architectural elements are critical for mitochondrial function. The yeast inner membrane protein Fcj1, called mitofilin in mammals, was reported to be preferentially located at CJs and crucial for their formation. Here we investigate the functional roles of individual domains of Fcj1. The most conserved part of Fcj1, the C-terminal domain, is essential for Fcj1 function. In its absence, formation of CJ is strongly impaired and irregular, and stacked cristae are present. This domain interacts with full-length Fcj1, suggesting a role in oligomer formation. It also interacts with Tob55 of the translocase of outer membrane β-barrel proteins (TOB)/sorting and assembly machinery (SAM) complex, which is required for the insertion of β-barrel proteins into the outer membrane. The association of the TOB/SAM complex with contact sites depends on the presence of Fcj1. The biogenesis of β-barrel proteins is not significantly affected in the absence of Fcj1. However, down-regulation of the TOB/SAM complex leads to altered cristae morphology and a moderate reduction in the number of CJs. We propose that the C-terminal domain of Fcj1 is critical for the interaction of Fcj1 with the TOB/SAM complex and thereby for stabilizing CJs in close proximity to the outer membrane. These results assign novel functions to both the C-terminal domain of Fcj1 and the TOB/SAM complex.


Retrospective serological analysis reveals presence of the emerging lagovirus RHDV2 in Australia in wild rabbits at least five months prior to its first detection.
The lagovirus rabbit haemorrhagic disease virus (RHDV) has been circulating in Australia since the mid-1990s when it was released to control overabundant rabbit populations. In recent years, the viral diversity of different RHDVs in Australia has increased, and currently four different types of RHDV are known to be circulating. To allow for ongoing epidemiological studies and impact assessments of these viruses on Australian wild rabbit populations, it is essential that serological tools are updated. To this end, reference sera were produced against all four virulent RHDVs (RHDV, RHDV2 and two different strains of RHDVa) known to be present in Australia and tested in a series of available immunological assays originally developed for the prototype RHDV, to assess patterns of cross-reactivity and the usefulness of these assays to detect lagovirus antibodies, either in a generic or specific manner. Enzyme-linked immunosorbent assays (ELISAs) developed to detect antibody isotypes IgM, IgA and IgG were sufficiently cross-reactive to detect antibodies raised against all four virulent lagoviruses. For the more specific detection of antibodies to the antigenically more different RHDV2, a competition ELISA was adapted using RHDV2-specific monoclonal antibodies in combination with Australian viral antigen. Archival serum banks from a long-term rabbit monitoring site where rabbits were sampled quarterly over a period of 6 years were re-screened using this assay and revealed serological evidence for the arrival of RHDV2 in this population at least 5 months prior to its initial detection in Australia in a dead rabbit in May 2015. The serological methods and reference reagents described here will provide valuable tools to study presence, prevalence and impact of RHDV2 on Australian rabbit populations; however, the discrimination of different antigenic variants of RHDVs as well as mixed infections at the serological level remains challenging.


Lactate normalization within 6 hours of bundle therapy and 24 hours of delayed achievement were associated with 28-day mortality in septic shock patients.
This study evaluated the prognostic ability of lactate normalization achieved within 6 and 24 h from septic shock recognition. Data from a septic shock registry from October 2015 to February 2017 were reviewed. The study included 2,102 eligible septic shock patients to analyze the prognostic ability of lactate normalization, defined as a follow-up lactate level <2 mmol/L within six hours of bundle therapy and within 24 hours of delayed normalization. The primary outcome was 28-day mortality. The overall 28-day mortality rate was 21.4%. The rates of lactate normalization within 6 and 24 h were significantly higher in the survivor groups than in the non-survivor group (42.4% vs. 23.4% and 60.2% vs. 31.2%; P<0.001, respectively). Multivariate logistic regression analysis showed that both 6- and 24-h lactate normalization were independent predictors (odds ratio [OR] 0.58, 95% confidence interval [CI] 0.45-0.75, p<0.001 and OR 0.42, 95% CI 0.33-0.54, p<0.001, respectively). When we could not achieve the lactate normalization, the sensitivity, specificity, positive, and negative predictive value to predict mortality were 76.6%, 42.4%, 26.5% and 87.0% respectively for 6-h normalization, and 68.8%, 60.2%, 32.0% and 87.7% respectively for 24-h normalization. Besides 6-h lactate normalization, 24-h delayed lactate normalization was associated with decreasing mortality in septic shock patients. Lactate normalization may have a role in early risk stratification and as a therapeutic target.


Assessment of Malaysia's Large-Scale Solar Projects: Power System Analysis for Solar PV Grid Integration.
Malaysia targets to become the second-largest producer of solar photovoltaic (PV) in the world by increasing the current output from 12% to 20% in 2020. The government also expects to achieve 45% reduction of greenhouse gas emission by 2030 through renewable energy mainly by solar PV. Large-scale solar (LSS) aims to produce 2.5 GW, which contributes to 10% of the nation's electricity demands. The LSS system is held back by the grid-scale integration, transmission, and distribution infrastructure. Thus, power system analysis is crucial to achieve optimization in LSS to power grid integration. This paper investigates various power system analysis models and recommends an optimized configuration based on Malaysia's LSS scenario. In stage 1, an optimal PV sizing is carried out based on real data of LSS installation in different locations. In stage 2, power analysis is carried out using to analyze the potential difference variation when connected to a nine-bus power system. The potential variation at each bus of the system is assessed and hence provides a feasibility statement on the most effective configurations for LSS-grid integration. This paper serves as the reference model for LSS-grid integration in Malaysia and is expected to be replicated in the other countries with similar conditions.


Drift estimation for single marker switching based imaging schemes.
In recent years, the diffraction barrier in fluorescence imaging has been broken and optical nanoscopes now routinely image with resolutions of down to 20 nm, an improvement of more than 10 fold. Because this allows imaging much smaller features and because all super-resolution approaches trade off speed for spatial resolution, mechanical instabilities of the microscopes become a limiting factor. Here, we propose a fully data-driven statistical registration method for drift detection and drift correction for single marker switching (SMS) imaging schemes, including a guideline for parameter choice and quality checks of the drift analysis. The necessary assumptions about the drift are minimal, allowing a model-free approach, but more specific models can easily be integrated. We determine the resulting performance on standard SMS measurements and show that the drift determination can be routinely brought to the range of precision achievable by fiducial marker-tracking methods.


One nanoprobe, two pathogens: gold nanoprobes multiplexing for point-of-care.
Gold nanoparticles have been widely employed for biosensing purposes with remarkable efficacy for DNA detection. Amongst the proposed systems, colorimetric strategies based on the remarkable optical properties have provided for simple yet effective sequence discrimination with potential for molecular diagnostics at point of need. These systems may also been used for parallel detection of several targets to provide additional information on diagnostics of pathogens. For the first time, we demonstrate that a single Au-nanoprobe may provide for detection of two distinct targets (pathogens) allowing colorimetric multi-target detection. We demonstrate this concept by using one single gold-nanoprobe capable to detect members of the Mycobacterium tuberculosis complex and Plasmodium sp., the etiologic agents of tuberculosis and malaria, respectively. Following characterisation, the developed gold-nanoprobe allowed detection of either target in individual samples or in samples containing both DNA species with the same efficacy. Using one single probe via the non-cross-linking colorimetric methodology it is possible to identify multiple targets in one sample in one reaction. This proof-of-concept approach may easily be integrated into sensing platforms allowing for fast and simple multiplexing of Au-nanoprobe based detection at point-of-need.


Evolutionary diversification of the Sm family of RNA-associated proteins.
The Sm family of proteins is closely associated with RNA metabolism throughout all life. These proteins form homomorphic and heteromorphic rings consisting of six or seven subunits with a characteristic central pore, the presence of which is critical for binding U-rich regions of single-stranded RNA. Eubacteria and Archaea typically carry one or two forms of Sm proteins and assemble one homomorphic ring per Sm protein. Eukaryotes typically carry 16 or more Sm proteins that assemble to form heteromorphic rings which lie at the center of a number of critical RNA-associated small nuclear ribonucleoproteins (snRNPs). High Sm protein diversity and heteromorphic Sm rings are features stretching back to the origin of eukaryotes; very deep phylogenetic divisions among existing Sm proteins indicate simultaneous evolution across essentially all existing eukaryotic life. Two basic forms of heteromorphic Sm rings are found in eukaryotes. Fixed Sm rings are highly stable and static and are assembled around an RNA cofactor. Flexible Sm rings also stabilize and chaperone RNA but assemble in the absence of an RNA substrate and, more significantly, associate with and dissociate from RNA substrates more freely than fixed rings. This suggests that the conformation of flexible Sm rings might be modified in some specific manner to facilitate association and dissociation with RNA. Diversification of eukaryotic Sm proteins may have been initiated by gene transfers and/or genome clashes that accompanied the origin of the eukaryotic cell itself, with further diversification driven by a greater need for steric specificity within increasingly complex snRNPs.


Loss of ETHE1, a mitochondrial dioxygenase, causes fatal sulfide toxicity in ethylmalonic encephalopathy.
Ethylmalonic encephalopathy is an autosomal recessive, invariably fatal disorder characterized by early-onset encephalopathy, microangiopathy, chronic diarrhea, defective cytochrome c oxidase (COX) in muscle and brain, high concentrations of C4 and C5 acylcarnitines in blood and high excretion of ethylmalonic acid in urine. ETHE1, a gene encoding a beta-lactamase-like, iron-coordinating metalloprotein, is mutated in ethylmalonic encephalopathy. In bacteria, ETHE1-like sequences are in the same operon of, or fused with, orthologs of TST, the gene encoding rhodanese, a sulfurtransferase. In eukaryotes, both ETHE1 and rhodanese are located within the mitochondrial matrix. We created a Ethe1(-/-) mouse that showed the cardinal features of ethylmalonic encephalopathy. We found that thiosulfate was excreted in massive amounts in urine of both Ethe1(-/-) mice and humans with ethylmalonic encephalopathy. High thiosulfate and sulfide concentrations were present in Ethe1(-/-) mouse tissues. Sulfide is a powerful inhibitor of COX and short-chain fatty acid oxidation, with vasoactive and vasotoxic effects that explain the microangiopathy in ethylmalonic encephalopathy patients. Sulfide is detoxified by a mitochondrial pathway that includes a sulfur dioxygenase. Sulfur dioxygenase activity was absent in Ethe1(-/-) mice, whereas it was markedly increased by ETHE1 overexpression in HeLa cells and Escherichia coli. Therefore, ETHE1 is a mitochondrial sulfur dioxygenase involved in catabolism of sulfide that accumulates to toxic levels in ethylmalonic encephalopathy.


The GroEL protein of Porphyromonas gingivalis accelerates tumor growth by enhancing endothelial progenitor cell function and neovascularization.
Porphyromonas gingivalis is a bacterial species that causes destruction of periodontal tissues. Additionally, previous evidence indicates that GroEL from P. gingivalis may possess biological activities involved in systemic inflammation, especially inflammation involved in the progression of periodontal diseases. The literature has established a relationship between periodontal disease and cancer. However, it is unclear whether P. gingivalis GroEL enhances tumor growth. Here, we investigated the effects of P. gingivalis GroEL on neovasculogenesis in C26 carcinoma cell-carrying BALB/c mice and chick eggs in vivo as well as its effect on human endothelial progenitor cells (EPC) in vitro. We found that GroEL treatment accelerated tumor growth (tumor volume and weight) and increased the mortality rate in C26 cell-carrying BALB/c mice. GroEL promoted neovasculogenesis in chicken embryonic allantois and increased the circulating EPC level in BALB/c mice. Furthermore, GroEL effectively stimulated EPC migration and tube formation and increased E-selectin expression, which is mediated by eNOS production and p38 mitogen-activated protein kinase activation. Additionally, GroEL may enhance resistance against paclitaxel-induced cell cytotoxicity and senescence in EPC. In conclusion, P. gingivalis GroEL may act as a potent virulence factor, contributing to the neovasculogenesis of tumor cells and resulting in accelerated tumor growth.


Whose Knowledge, Whose Development? Use and Role of Local and External Knowledge in Agroforestry Projects in Bolivia.
Agroforestry often relies on local knowledge, which is gaining recognition in development projects. However, how local knowledge can articulate with external and scientific knowledge is little known. Our study explored the use and integration of local and external knowledge in agroforestry projects in Bolivia. In 42 field visits and 62 interviews with agroforestry farmers, civil society representatives, and policymakers, we found a diverse knowledge base. We examined how local and external knowledge contribute to livelihood assets and tree and crop diversity. Projects based predominantly on external knowledge tended to promote a single combination of tree and crop species and targeted mainly financial capital, whereas projects with a local or mixed knowledge base tended to focus on food security and increased natural capital (e.g., soil restoration) and used a higher diversity of trees and crops than those with an external knowledge base. The integration of different forms of knowledge can enable farmers to better cope with new challenges emerging as a result of climate change, fluctuating market prices for cash crops, and surrounding destructive land use strategies such as uncontrolled fires and aerial fumigation with herbicides. However, many projects still tended to prioritize external knowledge and undervalue local knowledge-a tendency that has long been institutionalized in the formal educational system and in extension services. More dialogue is needed between different forms of knowledge, which can be promoted by strengthening local organizations and their networks, reforming agricultural educational institutions, and working in close interaction with policymakers.


Prolonged exposure vs eye movement desensitization and reprocessing vs waiting list for posttraumatic stress disorder in patients with a psychotic disorder: a randomized clinical trial.
The efficacy of posttraumatic stress disorder (PTSD) treatments in psychosis has not been examined in a randomized clinical trial to our knowledge. Psychosis is an exclusion criterion in most PTSD trials. To examine the efficacy and safety of prolonged exposure (PE) therapy and eye movement desensitization and reprocessing (EMDR) therapy in patients with psychotic disorders and comorbid PTSD. A single-blind randomized clinical trial with 3 arms (N = 155), including PE therapy, EMDR therapy, and waiting list (WL) of 13 outpatient mental health services among patients with a lifetime psychotic disorder and current chronic PTSD. Baseline, posttreatment, and 6-month follow-up assessments were made. Participants were randomized to receive 8 weekly 90-minute sessions of PE (n = 53), EMDR (n = 55), or WL (n = 47). Standard protocols were used, and treatment was not preceded by stabilizing psychotherapeutic interventions. Clinician-rated severity of PTSD symptoms, PTSD diagnosis, and full remission (on the Clinician-Administered PTSD Scale) were primary outcomes. Self-reported PTSD symptoms and posttraumatic cognitions were secondary outcomes. Data were analyzed as intent to treat with linear mixed models and generalized estimating equations. Participants in the PE and EMDR conditions showed a greater reduction of PTSD symptoms than those in the WL condition. Between-group effect sizes were 0.78 (P < .001) in PE and 0.65 (P = .001) in EMDR. Participants in the PE condition (56.6%; odds ratio [OR], 3.41; P = .006) or the EMDR condition (60.0%; OR, 3.92; P < .001) were significantly more likely to achieve loss of diagnosis during treatment than those in the WL condition (27.7%). Participants in the PE condition (28.3%; OR, 5.79; P = .01), but not those in the EMDR condition (16.4%; OR, 2.87; P = .10), were more likely to gain full remission than those in the WL condition (6.4%). Treatment effects were maintained at the 6-month follow-up in PE and EMDR. Similar results were obtained regarding secondary outcomes. There were no differences in severe adverse events between conditions (2 in PE, 1 in EMDR, and 4 in WL). The PE therapy and EMDR therapy showed no difference in any of the outcomes and no difference in participant dropout (24.5% in PE and 20.0% in EMDR, P = .57). Standard PE and EMDR protocols are effective, safe, and feasible in patients with PTSD and severe psychotic disorders, including current symptoms. A priori exclusion of individuals with psychosis from evidence-based PTSD treatments may not be justifiable. isrctn.com Identifier: ISRCTN79584912.


Anti-vascular endothelial growth factor for macular edema secondary to central retinal vein occlusion.
Central retinal vein occlusion (CRVO) is a common retinal vascular disorder in which macular edema (ME) may develop, with a consequent reduction in visual acuity. The visual prognosis in CRVO-ME is poor in a substantial proportion of patients, especially those with the ischemic subtype, and until recently there has been no treatment of proven benefit. Macular grid laser treatment is ineffective, and whilst a few recent randomized controlled trials (RCTs) suggest short-term gains in visual acuity with intravitreal steroids for patients with non-ischemic CRVO-ME, there is no established treatment for ischemic CRVO-ME. Anti-vascular endothelial growth factor (anti-VEGF) agents have been used to treat ME resulting from a variety of causes and may represent a treatment option for CRVO-ME. To investigate the effectiveness and safety of intravitreal anti-VEGF agents in the treatment of CRVO-ME. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Group Trials Register) (The Cochrane Library 2010, Issue 8), MEDLINE (January 1950 to August 2010), EMBASE (January 1980 to August 2010), Latin American and Caribbean Health Sciences Literature Database (LILACS) (January 1982 to August 2010), Cumulative Index to Nursing and Allied Health Literature (CINAHL) (January 1937 to August 2010), OpenSIGLE (January 1950 to August 2010), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com) and ClinicalTrials.gov (www.clinicaltrials.gov). There were no language or date restrictions in the search for trials. The electronic databases were last searched on 10 August 2010. We considered RCTs that compared intravitreal anti-VEGF agents of any dose or duration to sham injection or no treatment. We focused on studies that included individuals of any age or gender with unilateral or bilateral disease and a minimum of six months follow up. Secondarily, we considered non-randomized studies with the same criteria, but did not conduct a separate electronic search for these. Two review authors independently assessed trial quality and extracted data. We found two RCTs that met the inclusion criteria after independent and duplicate review of the search results. These RCTs utilized different anti-VEGF agents which cannot be assumed to be directly comparable. We, therefore, performed no meta-analysis. Evidence from these trials and from other non-randomized case series is summarized in this review. Ranibizumab and pegaptanib sodium have shown promise in the short-term treatment of non-ischemic CRVO-ME. However, effectiveness and safety data from larger RCTs with follow up beyond six months are not yet available. There are no RCT data on anti-VEGF agents in ischemic CRVO-ME. The use of anti-VEGF agents to treat this condition therefore remains experimental.


Electro-optic detection of continuous-wave mid-infrared radiation.
We demonstrate coherent detection of continuous-wave mid-infrared radiation. This radiation is produced by use of conventional difference-frequency mixing and detected via the linear electro-optic effect. The detection process allows for the simultaneous measurement of the amplitude and phase properties of the infrared field. Both processes require an amplitude-modulated optical beam that is derived from the superimposed output of two single-frequency lasers. With appropriate choice of lasers and nonlinear optical crystals, the technique may be applied to any wavelength throughout the far and mid infrared.


Pharmacokinetic interaction between verapamil and metoprolol in the dog. Stereochemical aspects.
The effect of verapamil co-administration on the hepatic first-pass clearance of metoprolol was investigated in dogs. Plasma concentration-time course of metoprolol enantiomers and urinary recovery of oxidative metabolites were determined after a single iv (0.51 mg/kg) and an oral (1.37 mg/kg) dose of deuterium-labeled pseudoracemic metoprolol, with or without concomitant administration of racemic verapamil (3 mg/kg). Verapamil inhibited both the systemic and oral clearance of metoprolol by about 50-70%. The first-pass effect of metoprolol was completely abolished after co-administration of verapamil, reflecting a marked alteration in the degree of hepatic extraction of metoprolol from intermediate to low. The hepatic clearance of metoprolol was slightly (S)-enantioselective (R/S ratio = 0.89 +/- 0.04) in control dogs. Inhibition of hepatic clearance of metoprolol by verapamil was selective towards (S)-metoprolol, such that the enantioselectivity in hepatic clearance toward (S)-metoprolol disappeared following verapamil co-administration (R/S ratio = 1.01 +/- 0.05). Urinary metabolite profiles indicated that O-demethylation and N-dealkylation were the major pathways of oxidative metabolism in the dog. alpha-Hydroxymetoprolol was a minor metabolite in urine. N-Dealkylation showed a strong preference for (S)-metoprolol, whereas O-demethylation and alpha-hydroxylation exhibited a modest selectivity toward (R)-metoprolol; hence, the slight (S)-enantioselectivity in the overall hepatic clearance. Comparison of metoprolol metabolite formation clearances in the absence or presence of verapamil co-administration showed that all three oxidative pathways were inhibited by 60-80%. The greater inhibition of hepatic clearance observed with (S)-metoprolol as compared to (R)-metoprolol was attributed to a significant (S)-enantioselective inhibition in the O-demethylation of metoprolol by verapamil.


In vivo functional expression of a screened P. aeruginosa chaperone-dependent lipase in E. coli.
Microbial lipases particularly Pseudomonas lipases are widely used for biotechnological applications. It is a meaningful work to design experiments to obtain high-level active lipase. There is a limiting factor for functional overexpression of the Pseudomonas lipase that a chaperone is necessary for effective folding. As previously reported, several methods had been used to resolve the problem. In this work, the lipase (LipA) and its chaperone (LipB) from a screened strain named AB which belongs to Pseudomonas aeruginosa were overexpressed in E. coli with two dual expression plasmid systems to enhance the production of the active lipase LipA without in vitro refolding process. In this work, we screened a lipase-produced strain named AB through the screening procedure, which was identified as P. aeruginosa on the basis of 16S rDNA. Genomic DNA obtained from the strain was used to isolate the gene lipA (936 bp) and lipase specific foldase gene lipB (1023 bp). One single expression plasmid system E. coli BL21/pET28a-lipAB and two dual expression plasmid systems E. coli BL21/pETDuet-lipA-lipB and E. coli BL21/pACYCDuet-lipA-lipB were successfully constructed. The lipase activities of the three expression systems were compared to choose the optimal expression method. Under the same cultured condition, the activities of the lipases expressed by E. coli BL21/pET28a-lipAB and E. coli BL21/pETDuet-lipA-lipB were 1300 U/L and 3200 U/L, respectively, while the activity of the lipase expressed by E. coli BL21/pACYCDuet-lipA-lipB was up to 8500 U/L. The lipase LipA had an optimal temperature of 30°C and an optimal pH of 9 with a strong pH tolerance. The active LipA could catalyze the reaction between fatty alcohols and fatty acids to generate fatty acid alkyl esters, which meant that LipA was able to catalyze esterification reaction. The most suitable fatty acid and alcohol substrates for esterification were octylic acid and hexanol, respectively. The effect of different plasmid system on the active LipA expression was significantly different. pACYCDuet-lipA-lipB was more suitable for the expression of active LipA than pET28a-lipAB and pETDuet-lipA-lipB. The LipA showed obvious esterification activity and thus had potential biocatalytic applications. The expression method reported here can give reference for the expression of those enzymes that require chaperones.


The Drosophila insulin pathway controls Profilin expression and dynamic actin-rich protrusions during collective cell migration.
Understanding how different cell types acquire their motile behaviour is central to many normal and pathological processes. Drosophila border cells represent a powerful model for addressing this issue and to specifically decipher the mechanisms controlling collective cell migration. Here, we identify the Drosophila Insulin/Insulin-like growth factor signalling (IIS) pathway as a key regulator in controlling actin dynamics in border cells, independently of its function in growth control. Loss of IIS activity blocks the formation of actin-rich long cellular extensions that are important for the delamination and the migration of the invasive cluster. We show that IIS specifically activates the expression of the actin regulator chickadee, the Drosophila homolog of Profilin, which is essential for promoting the formation of actin extensions and migration through the egg chamber. In this process, the transcription factor FoxO acts as a repressor of chickadee expression. Altogether, these results show that local activation of IIS controls collective cell migration through regulation of actin homeostasis and protrusion dynamics.


POLE mutations in families predisposed to cutaneous melanoma.
Germline mutations in the exonuclease domain of POLE have been shown to predispose to colorectal cancers and adenomas. POLE is an enzyme involved in DNA repair and chromosomal DNA replication. In order to assess whether such mutations might also predispose to cutaneous melanoma, we interrogated whole-genome and exome data from probands of 34 melanoma families lacking pathogenic mutations in known high penetrance melanoma susceptibility genes: CDKN2A, CDK4, BAP1, TERT, POT1, ACD and TERF2IP. We found a novel germline mutation, POLE p.(Trp347Cys), in a 7-case cutaneous melanoma family. Functional assays in S. pombe showed that this mutation led to an increased DNA mutation rate comparable to that seen with a Pol ε mutant with no exonuclease activity. We then performed targeted sequencing of POLE in 1243 cutaneous melanoma cases and found that a further ten probands had novel or rare variants in the exonuclease domain of POLE. Although this frequency is not significantly higher than that in unselected Caucasian controls, we observed multiple cancer types in the melanoma families, suggesting that some germline POLE mutations may predispose to a broad spectrum of cancers, including melanoma. In addition, we found the first mutation outside the exonuclease domain, p.(Gln520Arg), in a family with an extensive history of colorectal cancer.


Oxidized Phospholipids and Neutrophil Elastase Coordinately Play Critical Roles in NET Formation.
Neutrophil extracellular traps (NETs) are web-like structures consisting of decondensed chromatin DNA and contents of granules, such as myeloperoxidase (MPO) and neutrophil elastase (NE). NETs are usually released from neutrophils undergoing NETosis, a neutrophil-specific cell death mode characterized by the collapse and disappearance of cell membranes and nuclear envelopes. It is well known that production of reactive oxygen species (ROS) triggers NETosis and NET formation. However, details of intracellular signaling downstream of ROS production during NETosis and NET formation remains uncertain. Here, we demonstrated that the peroxidation of phospholipids plays a critical role in NETosis and NET formation induced by phorbol 12-myristate13-acetate (PMA) or immune complex in vitro and by lipopolysaccharide (LPS) in vivo. This phospholipid peroxidation is mediated by the enzymatic activity of MPO. On the other hand, NE, which was previously reported to be released from granules to cytosol by MPO during NET formation, is not required for either the peroxidation of phospholipids or the execution of NETosis, but contributes to chromatin decondensation and nuclear swelling independently of MPO-mediated oxidized phospholipids. Analysis of isolated nuclei clearly demonstrated that oxidized phospholipids and NE differently yet synergistically execute chromatin decondensation and nuclear swelling, and the subsequent release of nuclear contents. These findings indicate the dual roles of MPO in NETosis and NET formation, and provide new insight into the molecular mechanism of these phenomena.


Keap1 is a redox-regulated substrate adaptor protein for a Cul3-dependent ubiquitin ligase complex.
The bZIP transcription factor Nrf2 controls a genetic program that protects cells from oxidative damage and maintains cellular redox homeostasis. Keap1, a BTB-Kelch protein, is the major upstream regulator of Nrf2 and controls both the subcellular localization and steady-state levels of Nrf2. In this report, we demonstrate that Keap1 functions as a substrate adaptor protein for a Cul3-dependent E3 ubiquitin ligase complex. Keap1 assembles into a functional E3 ubiquitin ligase complex with Cul3 and Rbx1 that targets multiple lysine residues located in the N-terminal Neh2 domain of Nrf2 for ubiquitin conjugation both in vivo and in vitro. Keap1-dependent ubiquitination of Nrf2 is inhibited following exposure of cells to quinone-induced oxidative stress and sulforaphane, a cancer-preventive isothiocyanate. A mutant Keap1 protein containing a single cysteine-to-serine substitution at residue 151 within the BTB domain of Keap1 is markedly resistant to inhibition by either quinone-induced oxidative stress or sulforaphane. Inhibition of Keap1-dependent ubiquitination of Nrf2 correlates with decreased association of Keap1 with Cul3. Neither quinone-induced oxidative stress nor sulforaphane disrupts association between Keap1 and Nrf2. Our results suggest that the ability of Keap1 to assemble into a functional E3 ubiquitin ligase complex is the critical determinant that controls steady-state levels of Nrf2 in response to cancer-preventive compounds and oxidative stress.


The auditory P3 from passive and active three-stimulus oddball paradigm.
The aim of this study was the comparison of basic characteristics of the P3 subcomponents elicited in passive and active versions of the auditory oddball paradigm. A 3-stimulus oddball paradigm was employed in which subjects were presented with random sequence of tones while they performed a discrimination task in visual modality with no response to the tone (passive task) or responded to an infrequently occurring target stimulus inserted into sequence of frequent standard and rare non-target stimuli (active task). Results show that the magnitude of the frontal P3 response is determined by the relative perceptual distinctiveness among stimuli. The amplitude of frontal component is larger for the stimuli more deviated from the standard in both passive and active tasks. In all cases however, a maximum over central or fronto-central scalp regions was demonstrated. Moreover, amplitude of this component was influenced by the strength of attentional focus--a significantly larger response was obtained in the active session than in its passive counterpart. The apparent parietal P3 responses were obtained only in the active condition. The amplitude of this component is larger for the target than the non-target across all electrode sites, but both demonstrated a parietal maxima. This findings suggest that generation of early frontal P3 could be related to alerting activity of frontal cortex irrespective of stimulus context, while generation of later parietal P3 is related to temporo-parietal network activated when neuronal model of perceived stimulation and attentional trace are comparing.


Aging and replicative senescence have related effects on human stem and progenitor cells.
The regenerative potential diminishes with age and this has been ascribed to functional impairments of adult stem cells. Cells in culture undergo senescence after a certain number of cell divisions whereby the cells enlarge and finally stop proliferation. This observation of replicative senescence has been extrapolated to somatic stem cells in vivo and might reflect the aging process of the whole organism. In this study we have analyzed the effect of aging on gene expression profiles of human mesenchymal stromal cells (MSC) and human hematopoietic progenitor cells (HPC). MSC were isolated from bone marrow of donors between 21 and 92 years old. 67 genes were age-induced and 60 were age-repressed. HPC were isolated from cord blood or from mobilized peripheral blood of donors between 27 and 73 years and 432 genes were age-induced and 495 were age-repressed. The overlap of age-associated differential gene expression in HPC and MSC was moderate. However, it was striking that several age-related gene expression changes in both MSC and HPC were also differentially expressed upon replicative senescence of MSC in vitro. Especially genes involved in genomic integrity and regulation of transcription were age-repressed. Although telomerase activity and telomere length varied in HPC particularly from older donors, an age-dependent decline was not significant arguing against telomere exhaustion as being causal for the aging phenotype. These studies have demonstrated that aging causes gene expression changes in human MSC and HPC that vary between the two different cell types. Changes upon aging of MSC and HPC are related to those of replicative senescence of MSC in vitro and this indicates that our stem and progenitor cells undergo a similar process also in vivo.


Dissecting the role of the mitochondrial chaperone mortalin in Parkinson's disease: functional impact of disease-related variants on mitochondrial homeostasis.
The mitochondrial chaperone mortalin has been linked to neurodegeneration in Parkinson's disease (PD) based on reduced protein levels in affected brain regions of PD patients and its interaction with the PD-associated protein DJ-1. Recently, two amino acid exchanges in the ATPase domain (R126W) and the substrate-binding domain (P509S) of mortalin were identified in Spanish PD patients. Here, we identified a separate and novel variant (A476T) in the substrate-binding domain of mortalin in German PD patients. To define a potential role as a susceptibility factor in PD, we characterized the functions of all three variants in different cellular models. In vitro import assays revealed normal targeting of all mortalin variants. In neuronal and non-neuronal human cell lines, the disease-associated variants caused a mitochondrial phenotype of increased reactive oxygen species and reduced mitochondrial membrane potential, which were exacerbated upon proteolytic stress. These functional impairments correspond with characteristic alterations of the mitochondrial network in cells overexpressing mutant mortalin compared with wild-type (wt), which were confirmed in fibroblasts from a carrier of the A476T variant. In line with a loss of function hypothesis, knockdown of mortalin in human cells caused impaired mitochondrial function that was rescued by wt mortalin, but not by the variants. Our genetic and functional studies of novel disease-associated variants in the mortalin gene define a loss of mortalin function, which causes impaired mitochondrial function and dynamics. Our results support the role of this mitochondrial chaperone in neurodegeneration and underscore the concept of impaired mitochondrial protein quality control in PD.


Elastomeric negative acoustic contrast particles for capture, acoustophoretic transport, and confinement of cells in microfluidic systems.
We present a particle-based method for the immunospecific capture and confinement of cells using acoustic radiation forces. Ultrasonic standing waves in microfluidic systems have previously been used for the continuous focusing of cells in rapid screening and sorting applications. In aqueous fluids, cells typically exhibit positive acoustic contrast and are thus forced toward the pressure nodes of a standing wave. Conversely, elastomeric particles exhibit negative acoustic contrast and travel toward the pressure antinodes. We have developed a class of elastomeric particles that are synthesized in bulk using a simple nucleation and growth process, providing precise control over their size and functional properties. We demonstrate that the biofunctionalization of these particles can allow the capture and transport of cells to the pressure antinodes solely via acoustic radiation forces, which may enable new acoustics-based cell handling techniques such as the washing, labeling, and sorting of cells with minimal preparatory steps.


Comparative mapping of human alphoid sequences in great apes using fluorescence in situ hybridization.
Twenty-seven human alphoid DNA probes have been hybridized in situ to metaphase spreads of the common chimpanzee (PTR), the pigmy chimpanzee (PPA), and the gorilla (GGO) to investigate the evolutionary relationship between the centromeric regions of the great ape chromosomes. The surprising results showed that the vast majority of the probes did not recognize their corresponding homologous chromosomes. Alphoid sequences belonging to the suprachromosomal family 1 (chromosomes 1, 3, 5, 6, 7, 10, 12, 16, and 19) yielded very heterogeneous results: some probes gave intense signals, but always on nonhomologous chromosomes; others did not produce any hybridization signal. Almost all probes belonging to the suprachromosomal family 2 (chromosomes 2, 4, 8, 9, 13, 14, 15, 18, 20, 21, and 22) recognized a single chromosome: chromosome 11 (phylogenetic IX) in PTR and PPA and chromosome 19 (phylogenetic V) in GGO. Localization of probes of suprachromosomal family 3 (chromosomes 1, 11, 17, and X) was found to be substantially conserved in PTR and PPA, but not in GGO. Probe pDMX1, specific for the human X chromosome, was the only sequence detecting its corresponding chromosome in all three species. PPA chromosomes I, IIp, IIq, IV, V, VI, and XVIII were never labeled, even under low-stringency hybridization conditions, by the 27 alphoid probes used in this study. These results, with particular reference to differences found in the two related species PTR and PPA, suggest that alphoid centromeric sequences underwent a very rapid evolution.


Plant fitness assessment for wild relatives of insect resistant crops.
Risk assessments of new insect-resistant crops will need to estimate the potential for increased weediness of wild crop relatives as a consequence of gene flow. When field experiments are precluded by containment concerns, simulation experiments can identify hazards or measure expected differences between GMOs and parental plants. To measure plant fitness consequences of wild plant protection from Bt-susceptible herbivores, we used topical sprays of bacterial Bacillus thuringiensis larvacide (Bt) on Brassica rapa. Spontaneous crosses between B. rapa and Bt cole crops cannot be precluded, especially if adoption of Bt varieties leads to high exposure. We compared survivorship and seed output of B. rapa that were either protected from or exposed to Bt-susceptible Lepidoptera in the various conditions where hybrids are likely to occur: cultivated (disked) soil, uncultivated agricultural field margins, and nearby non-crop habitats (meadows and ruderal areas). The relative effect of herbivore protection varied among years, habitats, and populations of seedlings. In 2003-2004, Bt sprays did not result in lower herbivory on B. rapa, and plant fitness was not increased. However, in 2004-2006 B. rapa seedlings protected from Bt-susceptible herbivores lived 25% longer, on average, than those that were exposed to these herbivores. In addition, an average B. rapa seedling sprayed with Bt throughout its lifetime was twice as likely to produce siliques and had 251% of the seed output of a seedling exposed to herbivores. The fitness advantage of Bt-based plant protection was apparent in 2004-2005 in half the plants that experienced higher herbivory, and for 2005-2006, was more pronounced in agricultural habitats than in meadows with established, perennial vegetation and less disturbance. Positive effects of Bt-based plant protection and greater fitness in disturbed habitats suggest that crop-wild gene flow may benefit weed populations, and that field tests with herbivore exclusion/addition experiments are feasible alternatives when molecular containment of transgenes restricts field experiments with insect resistant crop-wild hybrids.


Expression of Paxillin is Correlated with Clinical Prognosis in Colorectal Cancer Patients.
The aim of this study was to investigate the expression of Paxillin in colorectal carcinoma and its significance in clinical prognosis. Tissue specimens from 242 colorectal cancer patients who underwent radical resection were collected in Shaanxi Provincial People's Hospital from 2010 to 2014. The mRNA levels of Paxillin in colorectal cancer tissue and tissue adjacent to carcinoma of 62 patients were measured by quantitative real-time PCR. Immunohistochemistry staining was used to detect the expression of Paxillin in 242 samples of paraffin-embedded tissues. The mRNA and protein level of Paxillin in colorectal cancer tissues were significantly higher than those in the tissue adjacent to carcinoma (P<0.001 and P=0.003, respectively). The expression of Paxillin was significantly correlated to tumor histological grade (P<0.001), tumor size (P=0.01), serum CA199 level (P<0.001), the clinical TNM stage (P<0.001), and distant metastasis (P<0.001). Survival analysis showed that the prognosis of the patients with high expression of Paxillin was poorer than those with low expression of Paxillin (P=0.03). Cox proportional hazards model with stepwise selection showed that age, Paxillin expression level, and the clinical TNM stage were independent prognostic factors influencing survival for patients (P=0.01, P=0.004 and P<0.001, respectively). Paxillin was expressed at significantly higher levels in colorectal cancer tissues and might serve as a potential prognostic indicator in patients with colorectal cancer.


Bee venom phospholipase A2 protects against acetaminophen-induced acute liver injury by modulating regulatory T cells and IL-10 in mice.
The aim of this study was to investigate the protective effects of phospholipase A2 (PLA2) from bee venom against acetaminophen-induced hepatotoxicity through CD4+CD25+Foxp3+ T cells (Treg) in mice. Acetaminophen (APAP) is a widely used antipyretic and analgesic, but an acute or cumulative overdose of acetaminophen can cause severe hepatic failure. Tregs have been reported to possess protective effects in various liver diseases and kidney toxicity. We previously found that bee venom strongly increased the Treg population in splenocytes and subsequently suppressed immune disorders. More recently, we found that the effective component of bee venom is PLA2. Thus, we hypothesized that PLA2 could protect against liver injury induced by acetaminophen. To evaluate the hepatoprotective effects of PLA2, C57BL/6 mice or interleukin-10-deficient (IL-10-/-) mice were injected with PLA2 once a day for five days and sacrificed 24 h (h) after acetaminophen injection. The blood sera were collected 0, 6, and 24 h after acetaminophen injection for the analysis of aspartate aminotransferase (AST) and alanine aminotransferase (ALT). PLA2-injected mice showed reduced levels of serum AST, ALT, proinflammatory cytokines, and nitric oxide (NO) compared with the PBS-injected control mice. However, IL-10 was significantly increased in the PLA2-injected mice. These hepatic protective effects were abolished in Treg-depleted mice by antibody treatment and in IL-10-/- mice. Based on these findings, it can be concluded that the protective effects of PLA2 against acetaminophen-induced hepatotoxicity can be mediated by modulating the Treg and IL-10 production.


Unpasteurized milk consumption and subsequent risk of cancer.
Concerns have been raised regarding the possible adverse health effects of consumption of unpasteurized milk and risk of cancer. We examined the association of self-reported intake of unpasteurized milk with subsequent risk of cancer in a large population-based cohort study. The Iowa Women's Health Study is a prospective cohort study of 55-69 year old women at baseline in 1986. Of the 41,836 women in the cohort at baseline, 22,808 cancer-free women completed the fourth follow-up questionnaire in 1997. Risk ratios (RR) and 95% confidence intervals (CI) were calculated using Cox proportional hazards regression analysis. Reported intake of unpasteurized milk was high: 59.2% consumed only as a child, 2.5% consumed only as an adult, and 16.5% consumed as a child and an adult. A total of 2,379 cancers were identified in the cohort at risk. Overall, the age-adjusted risk of cancer was lower among women who reported consumption of unpasteurized milk only as a child (RR = 0.90, 95% CI: 0.82-0.99) or as a child and an adult (RR = 0.85; 95% CI: 0.75-0.97). Adjustment for confounding factors attenuated these associations (RR = 0.92, 95% CI: 0.83-1.02 for consumption only as a child, and RR = 0.91; 95% CI: 0.79-1.04 for consumption as a child and an adult). These data suggest that consumption of unpasteurized milk does not increase risk of cancer.


Spinal abnormalities in classic bladder exstrophy.
To determine the frequency and clinical sequelae of significant spinal malformations in children born with classic bladder exstrophy. All patients evaluated or treated for classic bladder exstrophy at this institution were reviewed retrospectively. Radiographs or reports pertinent to the spine were retrieved and reviewed with a paediatric radiologist and all vertebral abnormalities categorized. Clinical charts of those with spinal anomalies were reviewed to determine any clinical neurological disorders associated with the radiographic findings. Of 423 patients with classic bladder exstrophy who were identified, 299 had radiographs or reports available for adequate review. Of these, 34 (11%) normal variants, e.g. spina bifida occulta and lumbarization or sacralization of vertebrae, were identified. Abnormalities of spinal curvature were identified in eight patients (2.7%), all with uncomplicated scoliosis. Spinal dysraphism was diagnosed in 12 patients (4%) and included myelomeningocele, lipomeningocele, scimitar sacrum, posterior laminal defects in two or more vertebrae, vertebral fusion and hemivertebrae. The one patient with myelomeningocele had clinical neurological dysfunction, giving an overall incidence of 0.3%. Spinal anomalies, excluding normal variants, occur in children born with classic bladder exstrophy at a rate of about 6.7%. The incidence of this association is much less than that for cloacal exstrophy. Although rare, neurological dysfunction can occur in the case of spinal dysraphism. Paediatric urologists and neurologists should be aware of this significant difference between patients with classic bladder and cloacal exstrophy to properly diagnose, evaluate and treat the attendant neurological problems.


Magnesium homeostasis and alcohol consumption.
Clinical and experimental evidence indicates alcohol consumption as one of the major causes of magnesium loss from several tissues. As a result of this loss, serum magnesium tends to decrease while urinary magnesium excretion increases 2-3 fold. Experimental data confirm that chronic consumption of 6% ethanol in the Lieber De-Carli diet for 3 weeks results in a marked decrease in total tissue magnesium content in rats. This decrease affects brain, liver and all skeletal muscle, including heart, to a varying extent. While a full picture of the implications of magnesium loss in these tissues is still lacking, it is becoming progressively clear that magnesium loss affects energy production, protein synthesis, cell cycle, and specific functions in the various organs affected. In addition, as magnesium regulated cytokine production and secretion, especially in macrophages and leukocytes, a major role of magnesium deficiency in alcohol-induced inflammatory processes can be envisioned. Considering all these various aspects together, it becomes apparent that magnesium loss may represent a predisposing factor to the onset of alcohol-induced pathologies including brain stroke, sarcopenia, cardiomyopathy, steatohepatitis and cirrhosis. The present review will attempt to clarify some of the mechanisms by which ethanol impairs magnesium transport and homeostasis in brain, brain vasculature, skeletal muscle, heart and liver cells, as a first step towards more mechanistic studies aimed at relating magnesium loss with the incurrence of short- and long-term ethanol-induced complications in these organs.


AC-Filtering Supercapacitors Based on Edge Oriented Vertical Graphene and Cross-Linked Carbon Nanofiber.
There is strong interest in developing high-frequency (HF) supercapacitors or electrochemical capacitors (ECs), which can work at the hundreds to kilo hertz range for line-frequency alternating current (AC) filtering in the substitution of bulky aluminum electrolytic capacitors, with broad applications in the power and electronic fields. Although great progress has been achieved in the studies of electrode materials for ECs, most of them are not suitable to work in this high frequency range because of the slow electrochemical processes involved. Edge-oriented vertical graphene (VG) networks on 3D scaffolds have a unique structure that offers straightforward pore configuration, reasonable surface area, and high electronic conductivity, thus allowing the fabrication of HF-ECs. Comparatively, highly conductive freestanding cross-linked carbon nanofibers (CCNFs), derived from bacterial cellulose in a rapid plasma pyrolysis process, can also provide a large surface area but free of rate-limiting micropores, and are another good candidate for HF-ECs. In this mini review, advances in these fields are summarized, with emphasis on our recent contributions in the study of these materials and their electrochemical properties including preliminary demonstrations of HF-ECs for AC line filtering and pulse power storage applications.


The biogenesis and characterization of mammalian microRNAs of mirtron origin.
Mirtrons, short hairpin pre-microRNA (miRNA) mimics directly produced by intronic splicing, have recently been identified and experimentally confirmed in invertebrates. While there is evidence to suggest several mammalian miRNAs have mirtron origins, this has yet to be experimentally demonstrated. Here, we characterize the biogenesis of mammalian mirtrons by ectopic expression of splicing-dependent mirtron precursors. The putative mirtrons hsa-miR-877, hsa-miR-1226 and mmu-miR-1224 were designed as introns within eGFP. Correct splicing and function of these sequences as introns was shown through eGFP fluorescence and RT-PCR, while all mirtrons suppressed perfectly complementary luciferase reporter targets to levels similar to that of corresponding independently expressed pre-miRNA controls. Splicing-deficient mutants and disruption of key steps in miRNA biogenesis demonstrated that mirtron-mediated gene knockdown was splicing-dependent, Drosha-independent and had variable dependence on RNAi pathway elements following pre-miRNA formation. The silencing effect of hsa-miR-877 was further demonstrated to be mediated by the generation of short anti-sense RNA species expressed with low abundance. Finally, the mammalian mirtron hsa-miR-877 was shown to reduce mRNA levels of an endogenous transcript containing hsa-miR-877 target sites in neuronal SH-SY5Y cells. This work confirms the mirtron origins of three mammalian miRNAs and suggests that they are a functional class of splicing-dependent miRNAs which are physiologically active.


Therapeutic targeting of the cyclin D3:CDK4/6 complex in T cell leukemia.
D-type cyclins form complexes with cyclin-dependent kinases (CDK4/6) and promote cell cycle progression. Although cyclin D functions appear largely tissue specific, we demonstrate that cyclin D3 has unique functions in lymphocyte development and cannot be replaced by cyclin D2, which is also expressed during blood differentiation. We show that only combined deletion of p27(Kip1) and retinoblastoma tumor suppressor (Rb) is sufficient to rescue the development of Ccnd3(-/-) thymocytes. Furthermore, we show that a small molecule targeting the kinase function of cyclin D3:CDK4/6 inhibits both cell cycle entry in human T cell acute lymphoblastic leukemia (T-ALL) and disease progression in animal models of T-ALL. These studies identify unique functions for cyclin D3:CDK4/6 complexes and suggest potential therapeutic protocols for this devastating blood tumor.


Oregon's Gun Relief Program for Adjudicated Mentally Ill Persons: The Psychiatric Security Review Board.
This article describes the State of Oregon's implementation of two programs designed to comply with federal gun laws regarding reporting individuals who have received mental health adjudications in criminal and civil courts. One mandate requires that states submit names of adjudicated individuals to the National Instant Criminal Background Check System (NICS) while the second requires that the state establish a qualifying gun restoration program for those disqualified from gun ownership. In 2009, Oregon's Legislature developed an administrative approach to gun restoration and assigned the responsibility for conducting these hearing to the Oregon Psychiatric Security Review Board (PSRB). The PSRB is a state administrative board that has existed since 1977 and has been primarily focused on the supervision and treatment of adult and juvenile insanity acquittees. The gun restoration program began in 2010, but to date has only received three completed petitions requesting restoration of firearm rights. The article concludes with a discussion that surmises why very few of the Oregonians who are listed in NICS have submitted petitions for relief.


Genetic and phenotypic diversity in breast tumor metastases.
Metastatic disease is the main cause of cancer-related mortality due to almost universal therapeutic resistance. Despite its high clinical relevance, our knowledge of how cancer cell populations change during metastatic progression is limited. Here, we investigated intratumor genetic and phenotypic heterogeneity during metastatic progression of breast cancer. We analyzed cellular genotypes and phenotypes at the single cell level by performing immunoFISH in intact tissue sections of distant metastatic tumors from rapid autopsy cases and from primary tumors and matched lymph node metastases collected before systemic therapy. We calculated the Shannon index of intratumor diversity in all cancer cells and within phenotypically distinct cell populations. We found that the extent of intratumor genetic diversity was similar regardless of the chromosomal region analyzed, implying that it may reflect an inherent property of the tumors. We observed that genetic diversity was highest in distant metastases and was generally concordant across lesions within the same patient, whereas treatment-naïve primary tumors and matched lymph node metastases were frequently genetically more divergent. In contrast, cellular phenotypes were more discordant between distant metastases than primary tumors and matched lymph node metastases. Diversity for 8q24 was consistently higher in HER2(+) tumors compared with other subtypes and in metastases of triple-negative tumors relative to primary sites. We conclude that our integrative method that couples ecologic models with experimental data in human tissue samples could be used for the improved prognostication of patients with cancer and for the design of more effective therapies for progressive disease.


Multiple Inherited Thrombophilic Gene Polymorphisms in Spontaneous Abortions in Turkish Population.
The aim of this study was to investigate the possible role of multiple inherited thrombophilic gene variations in women with unexplained spontaneous abortions. For this purpose, the Factor V Leiden (FVL) (rs6025), Prothrombin G20210A (rs1799963), MTHFR C677T (rs1801133), PAI-1 4G/5G (rs1799889), ACE I/D (rs1799752), eNOS E298D (rs1799983), and Apo E E2/E3/E4 (rs429358) polymorphisms were genotyped and correlated in spontaneously aborted fetal materials, their mothers and fertile women. Twenty three abortion materials, 22 women with ≥1 unexplained fetal loss, and 22 control subjects with at least two healthy term infants as a control group were studied. Target SNPs for each gene were analyzed by real time-PCR technique after genomic DNA isolation from maternal blood-EDTA, control group blood-EDTA and spontaneously aborted fetal tissues. Some cases had a single thrombophilic polymorphism, but the rest of the patients and fetal materials had combined thrombophilic polymorphisms. The PAI-1 4G/5G+4G/4G (P= 0.0017), 4G/4G (P= 0.0253), eNOS 894GT+894TT (P=0.0011) genotypes and T allele (P=0.0185), Apo E E3/E4+E3/E2+E2/E4 (P<0.0001) genotypes, E2 (P<0.0001) and E4 (P<0.0001) alleles were higher in spontaneously aborted fetal materials when compared to their mothers and control group. The Factor V Leiden rs6025, Prothrombin G20210A, MTHFR C677T, ACE I/D genotypes were different for each group but not statistically significant due to relatively small size of the samples (P>0.05). Our results indicated that combined thrombophilic gene variations may be associated with increased risk for spontaneous abortions and results need to be confirmed by larger sample size.


Video metrology using a single camera.
This paper presents a video metrology approach using an uncalibrated single camera that is either stationary or in planar motion. Although theoretically simple, measuring the length of even a line segment in a given video is often a difficult problem. Most existing techniques for this task are extensions of single image-based techniques and do not achieve the desired accuracy especially in noisy environments. In contrast, the proposed algorithm moves line segments on the reference plane to share a common endpoint using the vanishing line information followed by fitting multiple concentric circles on the image plane. A fully automated real-time system based on this algorithm has been developed to measure vehicle wheelbases using an uncalibrated stationary camera. The system estimates the vanishing line using invariant lengths on the reference plane from multiple frames rather than the given parallel lines, which may not exist in videos. It is further extended to a camera undergoing a planar motion by automatically selecting frames with similar vanishing lines from the video. Experimental results show that the measurement results are accurate enough to classify moving vehicles based on their size.


Analysis Of Medicare Advantage HMOs compared with traditional Medicare shows lower use of many services during 2003-09.
Enrollment in Medicare Advantage, the managed care program for Medicare beneficiaries, has grown rapidly, from 4.6 million enrollees in 2003 to 12.8 million by 2012, or 27 percent of all current Medicare beneficiaries. We analyzed utilization patterns of enrollees in Medicare Advantage health maintenance organization (HMO) plans compared to matched samples of people in traditional Medicare during 2003-09, to ascertain whether the HMO enrollees demonstrated different levels of use of services, which can be a hallmark of more integrated care. We found that utilization rates in some major categories, including emergency departments and ambulatory surgery or procedures, generally were 20-30 percent lower in Medicare Advantage HMOs in all years. Medicare Advantage HMO enrollees initially had lower rates of ambulatory visits and hospitalizations, although these rates converged by 2008; they also received about 10 percent fewer hip or knee replacements. In contrast, HMO enrollees underwent more coronary bypass surgery than patients in traditional Medicare. These findings suggest that overall, Medicare Advantage HMO enrollees might use fewer services and be experiencing more appropriate use of services than enrollees in traditional Medicare.


Association Between Depression, Anxiety, and Antidepressant Use With T-Wave Amplitude and QT-Interval.
Objectives: Cardiac repolarization may be affected by psychiatric disorders and/or antidepressant use, but evidence for this is inconclusive. This study examined the relationship between depressive and anxiety disorder and use of antidepressants with T-wave amplitude (TWA) and QT-interval. Methods: Data was obtained from the Netherlands Study of Depression and Anxiety (n = 1,383). Depression/anxiety was diagnosed with the DSM-IV based Composite International Diagnostic Interview. The use of tricyclic antidepressants (TCAs), selective serotonin and noradrenalin reuptake inhibitors (SNRIs), and selective serotonin reuptake inhibitors (SSRIs) was established. T-wave amplitude and QT-interval corrected for heart rate (QTc) were obtained from an ECG measured in a type II axis configuration. Results: Compared to controls, persons with depression or anxiety disorders did not show a significantly different TWA (p = 0.58; Cohen's d = 0.046) or QTc (p = 0.48; Cohen's d = -0.057). In spite of known sympathomimetic effects, TCA use (p = 0.26; Cohen's d = -0.162) and SNRI use (p = 0.70; Cohen's d = -0.055) were not significantly associated with a lower TWA. TCA use (p = 0.12; Cohen's d = 0.225) and SNRI use (p = 0.11; Cohen's d = 0.227) were also not significantly associated with a prolonged QTc. Conclusion: We did not find evidence that either depressive/anxiety disorder or antidepressant use is associated with abnormalities in TWA or QTc. Earlier found sympathomimetic effects of TCAs and SNRIs are not evident in these measures of cardiac repolarization.


A new class of quadruplex DNA-binding nickel Schiff base complexes.
We have prepared six new nickel Schiff base complexes via reactions of substituted benzophenones with different diamines in the presence of nickel(ii). These new complexes were then reacted with 1-(2-choroethyl)piperidine to afford a further six novel nickel(ii) Schiff base complexes bearing pendant ethylpiperidine groups. The complexes bearing the ethylpiperidine moieties had greater solubility in water, and were therefore suitable for use in DNA binding experiments. ESI mass spectra of solutions containing 4 and the parallel, tetramolecular quadruplex Q4, contained ions attributable to formation of non-covalent complexes. In contrast, no ions from non-covalent complexes were observed when the experiments were repeated using 4 and either a double stranded DNA (dsDNA) molecule (D2), or parallel Q1, a unimolecular quadruplex DNA (qDNA). The ESI-MS binding study also revealed that 14 has a significant ability to form non-covalent complexes with qDNA, but does not interact to the same extent with D2. This is supported by the large changes to the ellipticity of bands observed in the circular dichroism spectra of two different unimolecular qDNA molecules (c-kit1 and Q1), including the latter annealed under conditions designed to induce formation of alternative topologies (antiparallel and hybrid). In Fluorescent Indicator Displacement (FID) assays conducted using the new nickel complexes, 14 gave the lowest values of DC50 for experiments conducted with Q1 and Q4. Furthermore, 14 showed greater stabilisation of an antiparallel qDNA molecule in FRET assays than when the other new complexes were examined. These results highlight the potential of 14 as a lead complex for future structure/DNA binding investigations. This is reinforced by the results obtained from cytotoxicity studies performed using four of the nickel complexes, including 14, and Chinese hamster lung cancer (V79) cells, which gave IC50 values between 4 and 12 μM. These complexes were also shown to have the ability to induce apoptosis in the same cancer cell line.


An efficient continuous flow approach to furnish furan-based biaryls.
Suzuki cross-couplings of 5-formyl-2-furanylboronic acid with activated or neutral aryl bromides were performed under continuous flow conditions in the presence of (Bu)4N(+)F(-) and the immobilised t-butyl based palladium catalyst CatCart™ FC1032™. Deactivated aryl bromides and activated aryl chlorides were cross-coupled with 5-formyl-2-furanylboronic in the presence of (Bu)4N(+)OAc(-) using the bis-triphenylphosphine CatCart™ PdCl2(PPh3)2-DVB. Initial evidence indicates the latter method may serve as a universal approach to conduct Suzuki cross-couplings with the protocol successfully employed in the synthesis of the current gold standard Hedgehog pathway inhibitor LDE225.


The impact of health checks for people with intellectual disabilities: a systematic review of evidence.
Health checks for people with intellectual disabilities (ID) have been recommended as one component of health policy responses to the poorer health of people with ID. This review summarises evidence on the impact of health checks on the health and well-being of people with ID. Electronic literature searches and email contacts were used to identify literature relevant to the impact of health checks for people with ID. A total of 38 publications were identified. These involved checking the health of over 5000 people with ID from a range of countries including a full range of people with ID. Health checks consistently led to detection of unmet health needs and targeted actions to address health needs. Health checks are effective in identifying previously unrecognised health needs, including life-threatening conditions. Future research should consider strategies for optimising the cost-effectiveness or efficiency of health checks.


Mechanical spectra of glass-forming liquids. II. Gigahertz-frequency longitudinal and shear acoustic dynamics in glycerol and DC704 studied by time-domain Brillouin scattering.
This paper presents and discusses the temperature and frequency dependence of the longitudinal and shear viscoelastic response at MHz and GHz frequencies of the intermediate glass former glycerol and the fragile glass former tetramethyl-tetraphenyl-trisiloxane (DC704). Measurements were performed using the recently developed time-domain Brillouin scattering technique, in which acoustic waves are generated optically, propagated through nm thin liquid layers of different thicknesses, and detected optically after transmission into a transparent detection substrate. This allows for a determination of the frequency dependence of the speed of sound and the sound-wave attenuation. When the data are converted into mechanical moduli, a linear relationship between longitudinal and shear acoustic moduli is revealed, which is consistent with the generalized Cauchy relation. In glycerol, the temperature dependence of the shear acoustic relaxation time agrees well with literature data for dielectric measurements. In DC704, combining the new data with data from measurements obtained previously by piezo-ceramic transducers yields figures showing the longitudinal and shear sound velocities at frequencies from mHz to GHz over an extended range of temperatures. The shoving model's prediction for the relaxation time's temperature dependence is fairly well obeyed for both liquids as demonstrated from a plot with no adjustable parameters. Finally, we show that for both liquids the instantaneous shear modulus follows an exponential temperature dependence to a good approximation, as predicted by Granato's interstitialcy model.


Treatment of Osteoporosis in Australian Residential Aged Care Facilities: Update on Consensus Recommendations for Fracture Prevention.
Older people living in residential aged care facilities (RACFs) are at a higher risk of suffering fractures than the community-dwelling older population. The first Consensus Conference on Treatment of Osteoporosis in RACFs in Australia, held in Sydney in July 2009, aimed to address some of the issues relating to the treatment of older residents with osteoporosis in RACFs. Considering that the field of osteoporosis diagnosis and management has significantly advanced in the last 5 years and that new evidence has been generated from studies performed within RACFs, a Second Consensus Conference was held in Sydney in November 2014. An expert panel met in November 2014 in Penrith, NSW, Australia in an attempt to reach a consensus on diverse issues related to the treatment of osteoporosis at RACFs. Participants were selected by the scientific committee on the basis of their practice in an RACF and/or major published articles. The co-chairs distributed topics randomly to all participants, who then had to propose a statement on each topic for approval by the conference after a short, evidence-based presentation, when possible. This article provides an update on the most relevant evidence on osteoporosis in older people living in RACFs graded according to its level, quality, and relevance. As with the first consensus, it is hoped that this statement will constitute an important guide to aid physicians in their decision making while practicing at RACFs.


Surgical Resection of a Complex Multiple Scalp Avf without Preoperative Embolization: A Case Report.
Complex multiple arteriovenous fistula (AVF) of the scalp is an extremely rare disease and the traditional treatment is either endovascular embolization or surgical resection with preoperative endovascular embolization. Here, a 34-year-old male with pulsating mass and multiple tortuous vessels in front of the left tragus and scalp who was diagnosed as complex multiple arteriovenous fistula of the scalp is presented. Nearly total surgical resection of the lesion without preoperative intervention was performed. The deformity appearance and the buzzing sound in the patient's left ear were eradicated after operation. Therefore, surgical resection without preoperative embolization is still a promising method to treat complex multiple scalp AVF.